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WO1998050353A1 - Derives de vitamine d3 et procede de production - Google Patents

Derives de vitamine d3 et procede de production Download PDF

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Publication number
WO1998050353A1
WO1998050353A1 PCT/JP1998/001979 JP9801979W WO9850353A1 WO 1998050353 A1 WO1998050353 A1 WO 1998050353A1 JP 9801979 W JP9801979 W JP 9801979W WO 9850353 A1 WO9850353 A1 WO 9850353A1
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WO
WIPO (PCT)
Prior art keywords
methyl
compound
dihydroxy
added
vitamin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1998/001979
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English (en)
Japanese (ja)
Inventor
Hiroaki Takayama
Katsuhiro Konno
Toshie Fujishima
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Teijin Ltd
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Teijin Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Teijin Ltd filed Critical Teijin Ltd
Priority to US09/214,155 priority Critical patent/US6982257B1/en
Priority to AT98917742T priority patent/ATE229937T1/de
Priority to JP54791598A priority patent/JP3923090B2/ja
Priority to EP98917742A priority patent/EP0957088B1/fr
Priority to DE69810273T priority patent/DE69810273T2/de
Publication of WO1998050353A1 publication Critical patent/WO1998050353A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a novel Pitamin 13 3 derivative AND ITS preparation having a methyl group at the 2-position. More particularly, 1 useful as a osteoporosis therapeutic agents, 2 5 - relates methyl vitamin D 3 derivatives and their preparation - dihydric Dorokishi 2.
  • vitamin 13 3 As material activated vitamin 13 3 to control the metabolism of calcium Ya-phosphate salt in vivo, to the very important role it is widely recognized throughout the scientific literature patent publications and general ever. It is also a well-known fact that various vitamin D derivatives are used as therapeutic agents for dysbimin D metabolism, including osteoporosis and rickets.
  • hydroxyl group at the 1-position is a para-coordinate and the 2-position has a tri-coordinate substituent (3-hydroxypropyl or 3-fluoropropyl).
  • 1,25-dihydroxyvitamin D Three derivatives are known (Posner, H., J. Org. Chem., 1995, 60, 46 17).
  • 2-substituted vitamin 0 3 derivatives of preparation also mosquito ⁇ either position 1 shown in the above document, position 2, and 3 of the stereoisomers of the chiral carbon, of a particular combination It is only capable of producing isomers, and does not show a method for efficiently producing an arbitrary combination of isomers.
  • X represents a bromine atom or an iodine atom.
  • R 3 and R 4 each independently represent a hydrogen atom or a tri (C 1 -C 7 hydrocarbon) silyl group.
  • An object of the present invention relates to novel 1, 2 5-dihydroxy sheet having biological activity - in the child provides a 2-Mechirubi evening Min D 3 derivatives and their preparation.
  • R i and R 2 are each independently a hydrogen atom or a tri
  • (C ⁇ —C 7 alkyl) represents a silyl group.
  • the configurations of the asymmetric carbons at the 1-, 2-, and 3-positions are each independently para- or ⁇ -coordinate.
  • the object of the present invention is:
  • X represents a bromine atom or an iodine atom.
  • R 3 and R 4 each independently represent a hydrogen atom or a tri (C i -C hydrocarbon) silyl group.
  • tri-c 7 alkyl silyl group means a silyl group substituted by three independent linear or branched C 1 -C 7 alkyl groups, and among them, Trimethylsilyl, triethylsilyl, or t-butyldimethylsilyl is preferred.
  • 1,25-dihydroxy-2-methylbiamine D 3 derivative represented by the above formula (I) include:
  • the en-yne compound represented by the above formula (III), which is a starting material is substituted by its 3-, 4-, and 5-positions. It may be all stereoisomers derived from asymmetric carbon, or a mixture of these in any proportion, but their configuration is conserved during the reaction, and the 1,2,5-diphenyl has the corresponding configuration. Dorokishi 2 _ Mechirubi evening Min D 3 derivative is generated.
  • the palladium catalyst used in the present production method is a combination of a zero-valent or divalent organic palladium compound and a trisubstituted phosphorus compound.
  • an organic palladium compound tetrakis (triphenyl) Nylphosphine) palladium, tris (dibenzylideneacetate palladium), tris (dibenzylideneacetone) palladium chromate form, palladium acetate, etc.
  • the trisubstituted phosphorus compound include triphenylphosphine, Tributyl phosphine, etc.
  • the palladium catalyst combining both, tris (dibenzylideneacetone) palladium and triphenylphosphine, tris (dibenzylideneacetone) palladium chloroform and triphenylphosphine are preferable.
  • the mixing ratio is preferably 1: 1 to 1:10.
  • the molar ratio of the exomethylene compound represented by the above formula (II) to the enyne compound represented by the above formula (III) is desirably in the range of 1: 5-5: 1.
  • the palladium catalyst is used in an amount of 0.1 to 100 mol%, preferably 1 to 20 mol%, based on the exomethylene compound.
  • the reaction solvent is a non-polar solvent such as hexane, heptane or toluene, getyl ether, examples thereof include polar solvents such as tetrahydrofuran, dioxane, dimethoxetane, N, N-dimethylformamide, and acetonitrile, and a mixed solvent thereof. Of these, heptane and toluene are preferred. Furthermore, when these solvents are used in the reaction, it is desirable to carry out a treatment such as distillation or nitrogen substitution in advance. The reaction is carried out at a temperature ranging from room temperature to the boiling point of the solvent.
  • a base such as triethylamine, diisopropylethylamine or the like to carry out the reaction.
  • the amount of the base to be added it is preferable to use at least one equivalent of the reactant represented by the above formula (II) or the above formula (III), which is used in excess.
  • a deprotection reaction may be carried out if necessary.
  • R 2 can be converted to those of a hydrogen atom.
  • Such a deprotection reaction can be performed according to a known method (for example, Calveley, M. J .; Tetrahedron, 20, 4609, 1987, Ho, PT .; Tetrahedron Letters, 1623, 1978).
  • the deprotecting agent include tetrabutylammonium fluoride, lithium tetrafluoroporate, pyridium-P-troen sulfonate and camphorsulfonic acid.
  • exomethylene compound represented by the above formula (II) is synthesized according to a known method (B. Fernandez et al., J. Org. Chem., 1992, 57, 3173; J. Calverley et al., Chem. Lett., 1993, 3, 1845, A. Kutner et al., J. Org. Chem., 1988, 53, 3450).
  • Preferred specific examples of the enepine compound represented by the above formula ( ⁇ ) used in the production method of the present invention include:
  • the chain compound represented by the above formula (UI) used in the production method of the present invention can be synthesized, for example, according to the following scheme 1.
  • Scheme 1 In the above scheme 1, represents a tri-C 7 alkyl) silyl group or a ( ⁇ -C 7 alkyl) di (( ⁇ - ⁇ aryl) silyl group. Preferred examples thereof include a trimethylsilyl group and a triethylsilyl group.
  • R 2 represents a protecting group which forms an acetal together with the oxygen atom to be bonded, and a methoxymethyl group, a methoxyxetoxymethyl group, and t-butyldimethylsilyl group, and t-butyldiphenylsilyl group. And a tetrahydrobiranyl group are preferred.
  • This manufacturing method can be performed as follows. That is, the hydroxyl group of a commercially available optically active ester compound (IV) is silyl protected in the presence of a base to obtain a compound (V).
  • a silylating agent triethylsilyl chloride, t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride, triethylsilyl triflate, t-butyldimethylsilyl triflate and the like are preferably used.
  • the base a usual base such as triethylamine, 2,6-lutidine or imidazole is used.
  • the compound (V) is reduced with a hydride reducing agent to obtain the alcohol (VI).
  • a hydride reducing agent lithium aluminum hydride, diisobutyl aluminum hydride, and the like are preferable.
  • the generated hydroxyl group is oxidized with dimethyl sulfoxide / oxalyl chloride TPAP (tetrapropylammonium pentalate) ZN-methylmorpholine-N-oxide or the like to obtain an aldehyde (VII).
  • TPAP tetrapropylammonium pentalate
  • ZN-methylmorpholine-N-oxide or the like to obtain an aldehyde (VII).
  • the reaction is carried out to obtain a methylene compound (VIII).
  • the double bond is converted to an epoxide compound (IX) using a peroxide reagent such as hydrogen peroxide or metachloroperbenzoic acid, and then reacted with an acetylene derivative shown in the scheme in the presence of a base such as alkyllithium.
  • a peroxide reagent such as hydrogen peroxide or metachloroperbenzoic acid
  • an acetylene derivative shown in the scheme in the presence of a base such as alkyllithium.
  • Compound (X) is obtained.
  • Compound (X) is produced as a mixture (1: 1) of two diastereomers based on the stereoisomerism of the hydroxyl group, which can be easily separated and purified by ordinary separation operations such as column chromatography. Wear.
  • the configuration of the hydroxyl group of the separated diastereomer can be determined by measuring the MTPA ester of (R) — and (S) — and measuring i HNM R (Kusumi et al., Organic Synthesis Journal of the Chemical Society of Japan, 1996, 51, 462).
  • the desired en-yne compound represented by the above formula (III) can be produced optically pure. That is, the compound
  • the compound (XI) is obtained by protecting the hydroxyl group of (X) with acetal.
  • acetalizing agent methoxymethyl chloride, methoxetoxymethyl chloride, dihydroxypyran and the like are used.
  • fluoride reagent such as tetrabutylammonium fluoride
  • the generated primary hydroxyl group is converted to dimethyl sulfoxide / oxalyl chloride ⁇ TPA ⁇ (tetrapropylammonium pentapentenate).
  • -Methylmorpholine- Oxidized with N-oxide etc. to form aldehyde (XIII).
  • the aldehyde group is reacted with a vinyl Grignard reagent to obtain a compound (XIV).
  • the desired enyne compound (III) can be obtained by removing the acetal protecting group at the 5-position hydroxyl group under acidic conditions.
  • This compound (III) is formed as a mixture (1: 1) of two diastereomers based on the stereoisomerism of the hydroxyl group at the 3-position, which can be easily separated and purified by ordinary separation operations such as column chromatography. You.
  • the configuration of the hydroxyl group of the separated diastereomer can be determined by converting each of them into an acetonide formed by a hydroxyl group at the 3- or 5-position and measuring 13 C NMR (Rychnovsky, SD; J. Org. Chem., 1993, 58, 3511). Furthermore, it can lead to a protected silyl group at the 3- or 5-position hydroxyl group, if necessary.
  • silylating agent used herein examples include trimethylsilyl chloride, triethylsilyl chloride, t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride, triethylsilyl triflate, and t-butyldimethylsilyl triflate.
  • a flat base or the like is preferably used, and a normal base such as triethylamine, 2,6-lutidine or imidazole is used as the base.
  • reaction conditions such as the solvent and the reaction temperature in each reaction step of the above reaction formula, conditions usually used for each reaction are applied.
  • the steric configuration of the 4-position methyl group of the desired en-yne compound (III) is derived from the optically active ester compound (IV) used as the starting material, and in this synthesis route, This configuration is maintained throughout the reaction.
  • optically active S. ether compound (IV) used as the starting material by employing consistent reaction to maintain its configuration, key intermediates of vitamin D 3 compounds synthesized (III) optically pure Can be manufactured.
  • TBDPSC 1 is t-butyldiphenylsilyl chloride
  • DIBAL-H is diisobutylaluminum hydride
  • TPAP is tetrapropylammonium pentalutenate
  • NMO is N-methylmorpholine-N-oxide
  • mC PBA Is metaclo-perbenzoic acid
  • MT PAC 1 is hymethoxy-hyr — (trifluoromethyl) phenylacetyl chloride
  • DMAP is 4-dimethylaminopyridine
  • DHP is dihydroxypyran
  • T sOH is tosylic acid
  • TBAF stands for tetrabutylammonium fluoride
  • TBS OTf stands for t-butyldimethylsilyl triflate
  • TBDPS stands for t-butyldiphenylsilyl group
  • TBS stands for t-butyldimethylsilyl group
  • THP
  • the (4R) series can be prepared by a similar production method using the compound (52) obtained in the above scheme 2, and the (4S) series can be used as a starting material in the following optically active ester compound ( It can be synthesized by a similar production method using 6).
  • Oxalyl chloride (0.56 ml, 6.30 mmo 1, 3 eq.) was added to dichloromethane solution (4 ml) of DMSO (0.92 ml, 12.5 mmo 1, 6 eq.). In addition, the mixture was stirred at ⁇ 78 ° C. for 1 hour under an argon atmosphere. A solution of compound (59) (44 O mg, 2.08 mmo 1) in dichloromethane (10 ml) was added to the resulting solution at ⁇ 78 ° C., and the mixture was stirred for 30 minutes. 3 N (3.2 ml, 24 mmo 1, 12 equivalents) was added, and the mixture was stirred at —78-0 ° C. for 1 hour.
  • 2,6-Lutidine (0.18 ml, 1.5 mmol, 4 equivalents) was added to a dichloromethane solution (5 ml) of the compound (22) (58 mg, 0.376 mmo 1). Then, TBS ⁇ Tf (0.34 ml, 1.5 mmol, 4 equivalents) was added, and the mixture was stirred at 0 ° C. for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and the solvent was distilled off. The obtained crude product was purified by silica gel column chromatography (10 g, 2% AcOEt-hexane) to obtain colorless oil (38) (141 mg, 98%). Was.
  • the obtained compound (80) was dissolved in 1 ml of methanol, added with CSA (ll mg, 1 equivalent), and allowed to react overnight at room temperature under an argon atmosphere.
  • the reaction solution was evaporated, purified water was added, and the mixture was extracted with AcOEt.
  • the extract was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off.
  • Binding affinity for D 3 receptions evening one test compound is a dihydrazide mud carboxymethyl concentration which inhibits 50% binding of vitamin D 3 - [2 6, 2 7 - methyl-3 H] 1, 2 5 It was calculated and expressed as a relative intensity ratio when 1 / 25-dihydroxyvitamin D 3 was set to 100. The results are shown in the following table.
  • Compound VDR binding affinity Compound VDR binding affinity la, 25- (0H) 2 VD 3 100
  • the HL-60 cells used were purchased from a cell bank (Japanese Cancer Research Resource Bank, cell number: JCRB085). Cells were used as cryopreservation stocks to prevent changes in cell characteristics due to subculture, and those that had been thawed before starting the experiment and subculture started. The experiments were performed for one month to six months. For subculture, collect cells in suspension culture by centrifugation and add 1 Z to fresh culture solution.
  • NBT nitro blue tetrazolium
  • cytospin specimen was prepared. After air-drying, the cells were stained with Kernehichroth and the ratio of cells positive for NBT reduction activity was determined under a light microscope. The results are shown in the following table.
  • certain isomers have high affinity for vitamin D receptor and also for vitamin D binding protein,
  • the isomers show high affinity for the vitamin D receptor and low affinity for the vitamin D binding protein, indicating differences in affinity for both proteins. It can be used as a therapeutic.

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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Cette invention concerne des dérivés de vitamine D3 1,25-dihydroxy-2-méthyle qui correspondent à la formule générale (I) où R1 et R2 représentent chacun indépendamment hydrogène ou tri(C1-7alkyl)silyle. Les atomes de carbone asymétriques aux positions 1-, 2- et 3- possèdent chacun et indépendamment une configuration α ou β. Ces composés sont utiles en qualité de remèdes contre l'ostéoporose, le rachitisme, l'hyper-énergie thyroïdienne accessoire, etc.
PCT/JP1998/001979 1997-05-02 1998-04-30 Derives de vitamine d3 et procede de production Ceased WO1998050353A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US09/214,155 US6982257B1 (en) 1997-05-02 1998-04-30 Vitamin D3 derivative and its production method
AT98917742T ATE229937T1 (de) 1997-05-02 1998-04-30 Vitamin d 3? derivate und verfahren zur herstellung derselben
JP54791598A JP3923090B2 (ja) 1997-05-02 1998-04-30 ビタミンｄ３誘導体およびその製造法
EP98917742A EP0957088B1 (fr) 1997-05-02 1998-04-30 Derives de vitamine d3 et procede de production
DE69810273T DE69810273T2 (de) 1997-05-02 1998-04-30 Vitamin d 3? derivate und verfahren zur herstellung derselben

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9/114695 1997-05-02
JP09114695 1997-05-02

Publications (1)

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WO1998050353A1 true WO1998050353A1 (fr) 1998-11-12

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US (1) US6982257B1 (fr)
EP (1) EP0957088B1 (fr)
JP (1) JP3923090B2 (fr)
AT (1) ATE229937T1 (fr)
DE (1) DE69810273T2 (fr)
WO (1) WO1998050353A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3213092B2 (ja) 1991-11-01 2001-09-25 中外製薬株式会社 ２β位に置換基を有するビタミンＤ誘導体
WO2004067525A1 (fr) 2003-01-30 2004-08-12 Teijin Pharma Limited Dérivé de lactone de la vitamine d3
JP2011241170A (ja) * 2010-05-18 2011-12-01 Mercian Corp ビタミンｄ誘導体およびその製造方法

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2002066424A1 (ja) * 2001-02-23 2004-06-17 中外製薬株式会社 ２位に置換基を有するビタミンｄ誘導体
ATE420855T1 (de) * 2001-12-26 2009-01-15 Hiroaki Takayama 2-substituierte vitamin-d-derivate
JP4443205B2 (ja) * 2003-12-08 2010-03-31 ローム株式会社 電流駆動回路
US20070108105A1 (en) * 2005-11-16 2007-05-17 Burnett George A Upflow shakers and separators
GB202016614D0 (en) 2020-10-20 2020-12-02 King S College London Compounds

Citations (1)

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JPH0641059A (ja) * 1991-11-01 1994-02-15 Chugai Pharmaceut Co Ltd ２β位に置換基を有するビタミンＤ誘導体

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Publication number Priority date Publication date Assignee Title
US5446225A (en) 1992-02-05 1995-08-29 Board Of Trustees Of The Leland Stanford Junior Univ. Palladium catalyzed akylative cyclization useful in syntheses of Vitamin D and analogues
US5274142A (en) * 1992-03-12 1993-12-28 The Johns Hopkins University Vitamin D3 analogues
US5552392A (en) 1993-11-03 1996-09-03 Wisconsin Alumni Research Foundation Method of treating hypoparathyroidism with (20S) vitamin D compounds
US5877168A (en) * 1995-02-10 1999-03-02 Chugai Seiyaku Kabushiki Kaisha Vitamin D derivative with substituent at the 2β-position

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
JPH0641059A (ja) * 1991-11-01 1994-02-15 Chugai Pharmaceut Co Ltd ２β位に置換基を有するビタミンＤ誘導体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NAYERI S, ET AL.: "HIGH-AFFINITY NUCLEAR RECEPTOR BINDING OF 20-EPI ANALOGUES OF 1,25-DIHYDROXYVITAMIN D3 CORRELATES WELL WITH GENE ACTIVATION", JOURNAL OF CELLULAR BIOCHEMISTRY, WILEY-LISS INC, US, vol. 62, no. 03, 1 January 1996 (1996-01-01), US, pages 325 - 333, XP002917124, ISSN: 0730-2312, DOI: 10.1002/(SICI)1097-4644(199609)62:3<325::AID-JCB3>3.0.CO;2-T *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3213092B2 (ja) 1991-11-01 2001-09-25 中外製薬株式会社 ２β位に置換基を有するビタミンＤ誘導体
WO2004067525A1 (fr) 2003-01-30 2004-08-12 Teijin Pharma Limited Dérivé de lactone de la vitamine d3
US9073885B2 (en) 2003-01-30 2015-07-07 Teijin Pharma Limited Vitamin D3 lactone derivatives
JP2011241170A (ja) * 2010-05-18 2011-12-01 Mercian Corp ビタミンｄ誘導体およびその製造方法

Also Published As

Publication number Publication date
EP0957088A1 (fr) 1999-11-17
US6982257B1 (en) 2006-01-03
ATE229937T1 (de) 2003-01-15
JP3923090B2 (ja) 2007-05-30
EP0957088A4 (fr) 1999-11-17
DE69810273D1 (de) 2003-01-30
DE69810273T2 (de) 2003-08-28
EP0957088B1 (fr) 2002-12-18

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